The objective of this project is to examine the patterns and levels of naturally occurring DNA sequence variation in a variety of gene regions of D. melanogaster. Of particular interest is the effect of sequence alterations within and flanking the gene encoding the enzyme dopa decarboxylase (Ddc). No clear patterns between sequence variants and Ddc expression were observed, despite two-fold variation in Ddc enzyme activity among the 46 lines examined. Located adjacent to the 30 - 40 kilobases of DNA sequence containing a dense cluster of eight lethal-mutable genes (including Ddc) is an approximately 40 kilobase region in which, at most, one gene appears to be located. If mutations occur randomly throughout the genome, yet persist for any length of time only in regions where they produce little or no deleterious effect, we should see less variation in the dense cluster of genes than in the adjacent 40 kb region. Examination of DNA sequence variation by restriction mapping in this 80 kilobase region has revealed the opposite pattern. While we cannot rule out the selective maintenance of variation in the gene cluster, these results raise the possibility of increased insertion/deletion mutational activity in transcriptionally active regions although unknown constraints may exist in the nonvariable region. We have also examined variations in several other regions of the Drosophila genome including the genes for white, notch, rudimentary, amylase and an amylase pseudogene. Strong support has been obtained for the hypothesis that insertions/deletions, and transposable element insertions in particular, are deleterious.